This is an early phase research study looking at whether an experimental gene transfer, LVsh5/C46 (also known as Cal-1), is safe and if it can protect the immune system from the effects of HIV without the use of antiretroviral drugs.

Cal-1 is an experimental gene transfer agent designed to inhibit HIV infection through 2 active parts:

An Adaptive Phase I/II Study of the Safety of CD4+ T Lymphocytes and CD34+ Hematopoietic Stem/Progenitor Cells Transduced With LVsh5/C46, a Dual Anti-HIV Gene Transfer Construct, With and Without Conditioning With Busulfan in HIV-1 Infected Adults Previously Exposed to ART

Baseline demographic and clinical information, treatment, and duration of follow-up will be summarized by group and overall. Severity of clinical adverse events (AEs) and laboratory safety parameters will be graded according to DAIDS criteria. Numbers of individual AEs, in numbers of subjects, will be summarized by severity and treatment. AEs will also be summarized and aggregated by body system for clinical events. The worst severity of each clinical and laboratory AE, for each subject, will be summarized by treatment.

All grade 3 and 4 AEs, and any other events that lead to a subject ceasing trial follow-up, will be listed by treatment, with duration and resolution.

Feasibility measures include the number of manufacturing procedures successfully completed (i.e. complying with all release criteria); number of gene modified cells, as affected by CD4+ and CD34+ purity, transduction efficiency, and viability; and the number of target cells harvested.

Log10 HIV-1 RNA, CD4+ T lymphocyte count, CD4+ %, CD4:CD8 ratio, measures of Cal-1 marking/expression and thymopoiesis will be plotted over time for each individual subject, and will be summarized for each nominal study week.

Changes in Log10 HIV-1 RNA and CD4+ T lymphocyte count from baseline will be formally compared in all subjects.

Associations between feasibility and safety measures and secondary outcomes include:

It is estimated that 33 million individuals are currently infected with HIV. HIV/AIDS is a disease that impairs immune function, primarily by decreasing CD4+ T lymphocytes. The progression can be contained by daily dosing with antiretroviral therapy (ART) but there are side effects that can be treatment limiting, and the development of HIV drug resistance can force the physician to modify the ART regimen. There are no effective vaccines currently available for HIV.

LVsh5/C46 (also known as Cal-1) is a dual therapeutic, self-inactivating lentiviral vector that encodes for both a short hairpin RNA against the HIV-1 co-receptor CCR5 (sh5) and a HIV-1 fusion inhibitor, C46 and inhibits two processes required for HIV-1 infection:

Binding of the virus to the cellular CCR5 co-receptor and

Fusion of the virus with the host cell

The rationale is that Cal-1 introduced into hematopoietic progenitor/stem cells (HSPC) and mature CD4+ T lymphocytes will protect these cells and their progeny cells from HIV-1 infection and its pathogenic sequelae. This may provide a continuous means of controlling HIV-1 after a single or infrequent dose(s), thereby decreasing or delaying (partially or completely) the need for antiretroviral drug therapy.

Eligibility

Ages Eligible for Study:

18 Years to 65 Years

Genders Eligible for Study:

Both

Accepts Healthy Volunteers:

No

Criteria

Inclusion Criteria:

Prior to any study-related procedures, signed informed consent indicating that they understand the purpose, risks and procedures required for the study and are willing to participate in the study

ART or other antiretroviral therapy within 6 weeks of Screening 1 or any time during the pre-infusion period

Documented history of CD4+ T lymphocyte count < 250 cells/µl

Any previous or current AIDS-defining illnesses (CDC Category C), including AIDS-related dementia, with the exception of Kaposi's sarcoma confined to the skin

History of malignancy or systemic chemotherapy within the last 5 years (i.e., subjects with prior malignancy must be disease-free for 5 years), except curatively-treated basal cell carcinoma, cutaneous squamous cell carcinoma, or cervical or anal intra-epithelial neoplasia

Class II-IV heart failure, according to the New York Heart Association classification

Inadequate venous access for apheresis, as assessed at Screening 1

Current or planned systemic immunosuppressive or immunomodulatory medication

Taking warfarin, aspirin or any medication that is likely to affect platelet function or other aspects of blood coagulation, and unable to safely cease this medication for a period of 1 week prior, during, and 1 week after administration of G-CSF (a total period of 19 days)

Participation in any study involving any investigational drug or medical device within 30 days prior to Screening 1

Receipt of a vaccine for HIV-1 or any gene transfer product at any time

Prior treatment with recombinant G-CSF or busulfan or other stem-cell mobilizing or modulating agent within the previous 12 months

Known hypersensitivity to busulfan, G-CSF (Neupogen™) or E. coli-derived proteins

Subjects who will not accept transfusions of blood products

Pregnant or breast-feeding at any time between Screening 1 and Baseline (infusion)

History of alcohol or drug abuse within the 12 months prior to Screening 1

Inability to understand and provide informed consent

Contacts and Locations

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study.
To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below.
For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01734850